This project is designed to better delineate the pathology of B-cell differentiation and function in two malignancies of immunoglobulin (Ig) synthesizing cells, multiple myeloma (MM) and chronic lymphocytic leukemia (CLL). We have taken two approaches to this problem. First, we have adopted or initiated several methodologies designed to examine the immunoregulatory interactions between normal human T and B lymphocytes. Among these are the use of in vitro-active cyclophosphamide compounds which, in conjunction with murine monoclonal antibodies, functionally separate suppressor and cytotoxic precursors from mature effector populations. Similarly, we have developed a primary in vitro immunization assay for human peripheral lymphocytes to the hapten-carrier TNPSRBC as well as a method for producing human BxB hybridomas. In our second approach, we have developed new strategies designed to examine immunoregulation of malignant monoclonal B lymphocyte differentiation. Included in these methodologies are the production and use in clinical monitoring of heterologous and monoclonal anti-idiotypic antibodies, the ability to clone malignant MM, CLL and hairy cell leukemic lymphocytes, the most extensive (more than 100 patients) cytogenetic analysis and clinical correlations of CLL performed to date, and the definition of several functional immunoregulatory T-cell deficits in myeloma and CLL helper and suppressor activity as well as in autologous mixed lymphocyte reactions. Current efforts are aimed at utilizing the functional assays developed in the initial stages of this project to better define the immunoregulatory events and their pathology in MM and CLL at the level of the primary immune response to well-defined haptens, by the production of human monoclonal idiotypes and anti-idiotypes to TNP and phosphorylcholine, and by examining the regulatory role of lymphokines, anti-idiotypes and in vitro-active cychophosphamide compounds. Ultimately, these in vitro strategies and their clinical correlations should provide a foundation for more selective manipulation of immune function in MM and CLL patients with the potential for subsequent therapeutic application.